The National Resource for Cell Analysis and Modeling (NRCAM) develops new technologies for modeling cell biological processes. The technologies are integrated through Virtual Cell (VCell), a problem solving environment built on a central database and disseminated as a web application. The philosophy of VCell centers on model reuse, where a physiological model can be repeatedly interrogated and altered to address new hypotheses. For example, a given physiology can be simulated with 4 different methods, including deterministic or stochastic with either compartmental or explicit geometric representations (including experimental images). The VCell model building interface contains abstractions to explicitly support key biophysical mechanisms, including reaction kinetics, diffusion, flow, membrane transport, lateral membrane diffusion and electrophysiology. The technology research is divided into 4 projects. Biophysical Mechanisms will develop equations to address mechanisms not fully supported by the current VCell software: electrophysiology in neuronal geometries, cytoskeletal dynamics, mechanics and the combinatorial complexity of multi-molecular complexes. Numerical Algorithms will develop a new solver for systems with disparate spatial scales, a hybrid deterministic-stochastic spatial simulator, methods for spatially non-uniform electric potentials and a tool to simulate cells with moving boundaries. Data Driven Modeling proposes to significantly enhance VCell support for experimental data to both facilitate analysis of experimental data through tools like Virtual FRAP, and to permit direct comparison of simulation and experiment through parameter estimation and visualization technologies. The overall goal of the project on Model Building Blocks is to enhance VCell with features to aid in the model construction process; these include new software abstractions, links to external databases, rule-based modeling and maintaining support for community standards. A diverse group of 8 Driving Biological Projects and 10 collaborative projects from outstanding scientists are described. Through a rich repertoire of training, dissemination and outreach activities, NRCAM promotes a quantitative approach to cell biological research.